Two distinct HLA-DR3 haplotypes are associated with age related heterogeneity in Type 1 (insulin-dependent) diabetes

Summary Heterogeneity between two haplotypes in linkage disequilibrium with DR3: B8, C4AQOB1,BfS,DR3 and B18,C4A3BQO,BfF1,DR3, with regard to age at onset of Type 1 (insulin-dependent) diabetes mellitus, was investigated in 325 unrelated French patients (146 males and 179 females, age at onset 1 month to 29 years) who were genotyped for HLA-A, B, C, DR and Bf and 225 of whom were typed for the C4A, B complement components. A subgroup of 82 patients and 75 control subjects were tested for DR and DQ DNA restriction fragment length polymorphism. The distribution according to age at onset and the mean ages at onset were compared between patients bearing B8, DR3 (n=58), B18,DR3 (n=62) or other DR3 haplotypes (Bx, DR3, n=70), the haplotype segments C4AQOB1.DR3 (n=41) or C4A3BQO,DR3 (n = 52) and the C4 null alleles C4AQO (N=48) or C4BQO (n=112) alone. The B8,DR3 haplotype, its smaller segment C4AQOB1,DR3 or C4AQO alone were associated with age at onset after 6 years (p<0.01, <0.08 and <0.02 respectively); on the other hand, the B18,DR3 haplotype, its segment C4A3BQO,DR3 or C4BQO alone were significantly more frequent in patients aged less than 6 years at onset (p<0.02, <0.01 and <0.01 respectively). Accordingly, the mean age of onset was significantly lower in the latter compared with the former patiens (p<0.02, <0.02 and <0.01 respectively). No age-related variation was observed in BX,DR3 patients and their mean age of onset was intermediate. The observed age distributions were sex dependent: that of C4AQO was mainly observed in males, that of C4BQO in females. Restriction fragment length polymorphism analysis in 37 patients and 32 control subjects positive for DR3 showed distinct patterns which correlated with DR3 and/or DQW2 borne by the B8 (n=11) and the B18 (n=18) haplotypes, respectively. BX,DR3 subjects exhibited either one or the other of these patterns. In the patients, the B18 associated fragments were found in most cases; whereas the B8 associated pattern was more frequent in the control subjects. These results provide evidence that a heterogeneous genetic background associated with two subsets of DR3 and/or silent alleles of the fourth component of complement could account for differences in the clinical expression of Type 1 diabetes.     

Possible sodium and D-glucose cotransport in isolated jejunal epithelium of children

Some experimental data in human jejunum suggest a Na dependence for glucose absorption and a glucose dependence for Na absorption. However, the relationship between these two transport processes is not yet known. Na+ and D-glucose absorptions were, therefore, measured simultaneously, in vitro, in isolated jejunal mucosa of children. The results are as follows: 1) the steady-state accumulation of D-glucose (C/M glucose) is a function of the Na concentration gradient between cell and medium (C/M Na). In Ringer solution, C/M glucose = 3.97 and C/M Na = 0.29; in the presence of 10(-4) M ouabain, C/M glucose = 1.63 and C/M Na = 0.60, and in Na free solution, C/M glucose = 0.99. In the presence of phloridzin, C/M Na is not statistically different from that in Ringer, but C/M glucose is significantly decreased. 2) The influx of D-glucose at the luminal membrane is a function of Na concentration in the bathing solution; it has the value of 4.41 mumole/hr cm2 in the presence of Na and of 1.65 mumole/hr cm2 in absence of Na. 3) The short-circuit current is a saturable function of D-glucose and of 3-O-D-methylglucose. The Kt for glucose is 8.01 mM. These results support the concept of a coupling between Na and D-glucose absorptions at the luminal membrane of jejunal mucosa of children.     

Influence of glucose on the conversion of galactose into galactitol in the young adult

The levels of galactose and galactitol in the sera of 6 young adults after ingestion of 0.25 g/kg of galactose alone or with the same quantity of glucose were studied. The results showed that: glucose decreased significantly the galactosemia and galactitolemia observed after ingestion of galactose alone; repeated consumption on 4 consecutive days of galactose alone induced an increase in galactosemia, and more significantly in galactitolemia. The addition of glucose to galactose in the same conditions abolished these effects.     

Degenerative complications of diabetes

Even optimally treated insulin-dependent diabetes mellitus is responsible for a significant number of complications which impair daily activities and shorten life expectancy in most patients. The cause of these complications has been under investigation for many years. Substantial evidence supports the following 1) a role of high blood sugar levels which lead to glycosylation processes; 2) presence of disorders related to inadequate nutrition, and specifically excessive dietary intake of saturated fatty acids, rather than to insulin deficiency. Furthermore, hereditary factors may play an additional role (HLA haplotypes may promote the development of complications). Antibodies and/or hormonal factors may also be involved. Whatever the mechanisms involved, there is no doubt that every effort should be made to achieve normal blood sugar and lipid levels. But what is the optimal degree of control? What is the ideal diet? Is it necessary to risk severe hypoglycemia? Should insulin pumps be routinely used? Since many of these issues are as yet unresolved, there is a need for collecting valid data on long-term complications with several therapeutic regimens. Unfortunately, most of the many published statistical studies on these complications are virtually invalid. This fundamental issue is discussed. The authors urge diabetes mellitus specialists to use the actuarial method already used by oncologists for many years.